Transient ischemic attacks (TIA) are common, with an estimated 250,000-350,000 occurring each year in the US, an incidence about 30-40% that of stroke. Rapid recovery of cerebral ischemia is a defining characteristic of TIA and distinguishes it from completed stroke. This recovery defines a distinct pathophysiologic feature that generally indicates the presence of previously ischemic tissue still at risk: a characteristic that may be responsible for greater instability. In fact, numerous studies have shown that short-term risk of stroke is high after TIA, particularly in the first few days, even in patients treated with aspirin, the current standard of care. Antithrombotic therapy may play a distinct role in this acute pathophysiology. Effective therapies in those with TIA could significantly reduce the overall burden of stroke if initiated immediately. However, no large-scale trial has evaluated an acute intervention in patients with TIA. Platelet aggregation is an important contributing factor in cerebral ischemia, as in other forms of ischemia. Antiplatelet agents reduce the risk of ischemic stroke in a variety of settings with distinct pathophysiologies. Aspirin given to patients with a history of stroke or TIA reduces subsequent risk of stroke. Furthermore, aspirin initiated as an acute intervention after stroke reduces risk of death and recurrent stroke. Trials of clopidogrel in combination with aspirin after stroke/TIA suggest that the combination reduces risk of stroke but increases risk of major hemorrhage. However, the risk of thrombosis is extremely high in the acute period after TIA and risk of hemorrhage is expected to be lower than after a completed stroke, so the combination may be particularly effective and relatively safe in this setting. Even more compelling, clopidogrel in combination with aspirin reduced the 90-day risk of stroke by 36% compared to aspirin alone in a pilot trial of 392 patients treated acutely after minor stroke or TIA, and it was well tolerated. Antiplatelet therapy has never been tested in a pivotal trial as an acute intervention after TIA, a setting with distinct pathophysiology that may favor the use of this class of agents. We are proposing the Platelet-Oriented Inhibition in New TIA (POINT) trial. The Primary Specific Aim of this randomized, double-blind, multicenter clinical trial is to determine whether clopidogrel 75 mg/day by mouth after a loading dose of 600 mg is effective in reducing the 90-day risk of stroke, myocardial infarction, and vascular death (the primary composite outcome) when initiated within 12 hours of TIA onset in patients receiving aspirin 50-325 mg/day. We plan to enroll 4150 patients at 150 centers over 4 years. We will work with the NINDS Neurologic Emergencies Treatment Trials (NETT) network and the Clinical Research Collaboration (CRC), which will be responsible for site monitoring and data management. There are few conditions as common and ominous as TIA for which no pivotal randomized trial has been performed. In fact, it is startling that proposing such a trial remains highly innovative given the obvious need in this area. PUBLIC HEALTH RELEVANCE: Transient ischemic attacks (TIAS) are common, with an estimated 250,000-350,000 occurring each year in the US, and the risk of stroke risk is very high soon afterwards in spite of the best available treatments. In this randomized, blinded, multicenter trial, we will evaluate clopidogrel, a drug that blocks blood clotting, as a treatment to reduce risk of stroke and heart attack after TIA in patients also prescribed aspirin. If the trial is positive, treatment with clopidogrel could reduce the stroke burden in the US and substantially reduce costs of care.